Change In Seizure Frequency Research Articles

Zonisamide as Adjunctive Therapy for Adults with Partial-Onset Epileptic Seizures: An Efficacy and Safety Review

Purpose To provide a review of randomized controlled trials (RCTs) on the efficacy and safety of zonisamide as an adjunctive treatment for partial-onset seizures in epilepsy patients ages 12 years and above. Methods Medline literature search for published double-blind RCTs involving zonisamide as adjunctive treatment for simple partial, complex partial, and secondarily generalized tonic-clonic seizures. Results Four RCTs comprising a total of 841 patients with medically-intractable simple partial, complex partial and secondarily generalized tonic-clonic seizures were published between the years 1993 and 2005. Zonisamide doses included 0, 100, 300, 400, 500 and 600 mg/day. Median change in frequency of all partial seizures compared to baseline was a 26.9%–51.3% decrease at zonisamide doses of 400–600 mg/day compared to a 4.7% increase to 18.1% decrease with placebo. Responder rates (>50% reduction) for all partial seizures was 26.9%–52.5% for zonisamide at these doses versus 9.8%–22% reduction for placebo. A dose-response relationship was noted up to 500 mg/day. Seizure free rates during the double blind treatment phases were 5%–6.2% for full-dose zonisamide versus 2% for placebo in two of the RCTs. Side effects were mostly CNS in type: somnolence, fatigue, dizziness and ataxia. Mild weight loss and anorexia were reported. Symptomatic renal calculi and serious rashes were not reported, but a few cases of possible stones seen transiently on ultrasound occurred, in these 4 RCTs. Four deaths occurred: none were taking zonisamide, and two appeared to be related to suffocation during seizures. Suicidal ideation and behavior occurred equally in placebo- and ZNS-treated subjects. Post-approval information suggests the rare occurrences of metabolic acidosis, oligohydrosis and hyperthermia, more commonly in children. Conclusion Zonisamide at a daily dose up to 600 mg is effective and generally well tolerated as adjunctive therapy in adolescents and adults with refractory partial-onset seizures.

Letter: Vagus nerve stimulation and cardiac asystole

To the Editors: This month’s issue of Epilepsia highlights important issues regarding refractory epilepsy, cardiac dysfunction, and vagus nerve stimulation (VNS). In a Brief Communication (Iriarte et al., 2009), a patient with refractory epilepsy and VNS developed heart block during status epilepticus 9 years after asymptomatic function. In a Letter from the same issue, Schuurman & Beukers, 2009 report asystole during intraoperative lead testing. Asystole has been known to occur intraoperatively (Tatum et al., 1999), with a prior case described extraoperatively (Amark et al., 2007). While underreporting could exist, there are nearly 50,000 implants worldwide, with reported cases still approximating an incidence of <0.1% (Data on file, Cyberonics, 2009). Fortunately, excessive death in patients with VNS has not been encountered (Annegers et al., 2000). However, in contrast sudden unexpected death in epilepsy (SUDEP) occurs at a rate of 1 per 150 person-years with uncontrolled seizures (Thompson et al., 2005), and is more prevalent and a significant risk. Delayed arrhythmia reported by Iriarte et al. (2004) bears several points worth noting. First, the patient had a VNS model 101 functioning with a current intensity of 1.75 mA, which after 9 years of use could have manifest erratic function representing end-of-service and resulting in status. Earlier models had limited predictability of generator battery failure (Tatum et al., 2004). Secondly, status epilepticus can produce a chronic alteration in cardiac sympathovagal balance (Metcalf et al., 2009) and could have predisposed to arrhythmia (Ali et al., 2004). Lastly, intravenous and γ-aminobutyric acid (GABA)ergic antiepileptic drugs (AEDs) may have provided an added “inhibitory” response, further taxing an already compromised cardiac reserve. Therefore, it seems plausible that asystole reflect factors unique to the operating room (OR) setting at implant, although may include multiple factors postimplant. In >250 implants, we have encountered two cases of asystole. Both occurred in the OR, with the first patient reported in 1999, and a second that occurred in 2008 during battery replacement. A 19-year-old woman had a single 15-s asystole that occurred in the OR in 2008 during the second cycle of stimulation. Despite initial deactivation, this patient was subsequently successfully reactivated postoperatively in the intensive care unit without recurrent arrhythmia thereafter. These reports emphasize the importance of continued vigilance for the patients with refractory epilepsy and VNS. Given the at-risk population, postmarketing surveillance should exist for all treatments. General suggestions for clinicians using VNS include ensuring patients are nonsurgical candidates, maintaining a heightened awareness during initial lead testing, and minimizing polypharmacy. Specific recommendations include careful observation for a change in seizure semiology, frequency, or intensity to suggest an alternate diagnosis or end of service, identifying concomitant heart disease, and early treatment of comorbidities that could predispose to arrhythmia. We also minimize inhalant neuro-anesthesia during surgery, repeat the lead test if bradycardia or asystole occurs, and deactivate the VNS prior to elective surgery. Despite isolated cases of arrhythmia, the overall effectiveness of VNS has “survived” for more than 10 years. We agree with Schuurman and Beukers that “it would be unfortunate…if VNS surgery was aborted (or deferred) as a result of these data.” With all treatments, the balance between risk and benefit must be weighted. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Conflict of interest: Dr. Tatum has received honoraria from Cyberonics Inc.

Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: A randomized placebo‐controlled trial

To evaluate efficacy and safety of adjunctive treatment with rufinamide 1600 mg twice daily in subjects aged > or = 16 years with refractory partial seizures. This double-blind, placebo-controlled, randomized, parallel-group, multicenter trial included an 8-week baseline phase and a 13-week double-blind phase. Treatment was initiated with rufinamide 400 mg twice daily or placebo; rufinamide was titrated to 1600 mg twice daily. Percentage change in partial seizure frequency was the primary outcome measure. Secondary outcome measures included total partial seizure frequency and the percentage of subjects experiencing a >/=50% reduction in partial seizure frequency. Three hundred thirteen subjects were randomized; 156 subjects received rufinamide and 157 received placebo. Rufinamide-treated subjects experienced a 20.4% median reduction in partial seizure frequency relative to baseline, while placebo-treated subjects had an increase of 1.6% (p = 0.02). Exclusion of subjects taking carbamazepine in a post hoc analysis resulted in a reduction of 29.2% versus 0.7% in the placebo group (p = 0.05), whereas the treatment difference in subjects taking carbamazepine was not significant. Of rufinamide-treated subjects, 28.2% experienced a > or = 50% decrease in partial seizure frequency versus 18.6% of placebo-treated subjects (p = 0.04). The most common adverse events associated with rufinamide treatment were dizziness, nausea, diplopia, and ataxia; they occurred primarily during the titration phase. Adjunctive therapy with rufinamide 3200 mg/day compared with matching placebo demonstrated efficacy and was generally well tolerated in adults with partial seizures. Further study of this agent in adults with partial seizures taking a range of baseline AEDs is warranted.

Meta-Analysis of EEG Biofeedback in Treating Epilepsy

About one third of patients with epilepsy do not benefit from medical treatment. For these patients electroencephalographic (EEG) biofeedback is a viable alternative. EEG biofeedback, or neurofeedback, normalizes or enhances EEG activity by means of operant conditioning. While dozens of scientific reports have been published on neurofeedback for seizure disorder, most have been case series with too few subjects to establish efficacy. The purpose of this paper is to meta-analyze existing research on neurofeedback and epilepsy. We analyzed every EEG biofeedback study indexed in MedLine, PsychInfo, and PsychLit databases between 1970 and 2005 on epilepsy that provided seizure frequency change in response to feedback. Sixty-three studies have been published, 10 of which provided enough outcome information to be included in a meta-analysis. All studies consisted of patients whose seizures were not controlled by medical therapies, which is a very important factor to keep in mind when interpreting the results. Nine of 10 studies reinforced sensorimotor rhythms (SMR) while 1 study trained slow cortical potentials (SCP). All studies reported an overall mean decreased seizure incidence following treatment and 64 out of 87 patients (74%) reported fewer weekly seizures in response to EEG biofeedback. Treatment effect was mean log (post/pre) where pre and post represent number of seizures per week prior to treatment and at final evaluation, respectively. Due to prevalence of small groups, Hedges's g was computed for effect size. As sample heterogeneity was possible (Q test, p=.18), random effects were assumed and the effect of intervention was -0.233, SE = 0.057, z = -4.11, p<.001. Based on this meta-analysis, EEG operant conditioning was found to produce a significant reduction on seizure frequency. This finding is especially noteworthy given the patient group, individuals who had been unable to control their seizures with medical treatment.

Management issues for women with epilepsy—Focus on pregnancy (an evidence‐based review): I. Obstetrical complications and change in seizure frequency

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy. The committee evaluated the available evidence according to a structured literature review and classification of relevant articles. For WWE who are taking antiepileptic drugs (AEDs), there is probably no substantially increased risk (>2 times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (>1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. WWE should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84-92%) of remaining seizure-free during pregnancy. WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery.

Efficacy, safety, and tolerability of the low glycemic index treatment in pediatric epilepsy

To report the efficacy, safety, and tolerability of the low glycemic index treatment (LGIT) in pediatric epilepsy. A retrospective chart review was performed on patients initiating the LGIT at the Massachusetts General Hospital between January 2002 and June 2008. Demographic and clinical information including seizure type, baseline seizure frequency, medications, blood chemistries, side effects, and anthropometrics were collected. Initiation of the LGIT was done in an outpatient setting. Patients were educated by a dietitian to restrict foods with high glycemic index and to limit total daily carbohydrates to 40-60 g. Change in seizure frequency was assessed at 1-, 3-, 6-, 9-, and 12-month follow-up intervals. Seventy-six children were included in the study. Eighty-nine percent had intractable epilepsy (>or=3 antiepileptic drugs). A greater than 50% reduction from baseline seizure frequency was observed in 42%, 50%, 54%, 64%, and 66% of the population with follow-up available at 1, 3, 6, 9, and 12 months, respectively. Increased efficacy was correlated with lower serum glucose levels at some time points, but not with beta-hydroxybutyrate (BOHB) changes or ketosis status at any time point. Only three patients reported side effects (transient lethargy). Blood urea nitrogen (BUN) was elevated in approximately one-third of follow-up laboratory studies. No significant changes were seen in body mass index (BMI) or BMI z-score at any follow-up interval. The most cited reason for treatment discontinuation was the restrictiveness of the diet, in 18 patients (24%). The LGIT was associated with reduced seizure frequency in a large fraction of patients, with limited side effects.

Practice Parameter update: Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): Obstetrical complications and change in seizure frequency

To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy in WWE compared to other women, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy. A 20-member committee including general neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and February 2008. For WWE taking antiepileptic drugs, there is probably no substantially increased risk (greater than two times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (greater than 1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. Seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84%-92%) of remaining seizure-free during pregnancy. Women with epilepsy (WWE) should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high rate (84%-92%) of remaining seizure-free during pregnancy (Level B). However, WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery during pregnancy (Level C).

Lamotrigine–valproic acid combination therapy for medically refractory epilepsy

A retrospective study of lamotrigine (LTG)-valproic acid (VPA) combination therapy in medically refractory epilepsy. Patients were identified with an adult epilepsy clinic database and were included if they had been on LTG-VPA combination therapy for at least 6 months. Patient demographics and information about epilepsy type, severity, and degree of medical intractability were obtained by retrospective chart review. The primary outcome measure was change in baseline seizure frequency, and patients were stratified into three groups: (i) seizure-free, (ii) improved (at least 50% reduction in baseline seizure frequency), and (iii) not improved. Thirty-five patients met all inclusion-exclusion criteria. Epilepsy type was generalized in 25 patients (71%) and partial in 10 patients (29%). Before LTG-VPA treatment, 27 of 35 (77%) experienced disabling seizures on a monthly basis, and 17 of 35 (49%) of patients had at least one disabling seizure per week. Patients had previously failed treatment with a median of five antiepileptic drugs (AEDs), alone or in combination. With LTG-VPA therapy, 18 (51.4%) remained completely seizure-free, four (11.4%) were improved, and 13 (37.1%) were unimproved. Median follow-up was 42 months. Of the 22 patients who improved, 11 had previously failed LTG and VPA monotherapy. There was no significant difference between improved and unimproved patients with respect to demographics, epilepsy type or severity, or number of previously failed AEDs. The combination of LTG and VPA should be considered in patients with medically refractory epilepsy. The effectiveness of this combination appears to be independent of epilepsy type or patient demographics.

Pregabalin as adjunctive therapy for partial epilepsy: An audit study in 96 patients from the South East of England

Introduction Pregabalin (PGB) was licensed in the EU in 2004 as an adjunctive therapy in partial epilepsy. It is also licensed for neuropathic pain and generalised anxiety. Aims To identify the clinical usefulness and side effects of add-on PGB in out-patient epilepsy clinics. Methods We performed an audit on 96 consecutive patients (44 male) prescribed PGB for refractory epilepsy. Mean follow-up, for those who remained on PGB, was 23 months (range 12–39 months). Results Fifty patients remained on PGB, 37 of whom reported clear improvement in seizure frequency. Among these 37 patients, 1 was seizure free for 15 months; 29 had a seizure reduction of >50%; and 7 improved by <50%. Eight patients reported a decrease in seizure severity without change in seizure frequency. Nine patients reported an incidental improvement in anxiety. Side effects were reported by 25 patients out of the 50 patients still on treatment: 12 reported drowsiness or tiredness, 8 weight gain, 7 dizziness, 2 headache, 2 cognitive side effects, 1 irritability, 1 itchiness, 1 anxiety, and 1 transient rash. Among the 46 patients who discontinued treatment, 9 had worsening of seizure frequency, 27 lack of efficacy and 9 intolerable side effects necessitating withdrawal (4 dizziness or drowsiness, 2 weight gain, 1 peripheral oedema, 1 pain in arms and legs, 1 irritability and cognitive side effects). One patient had a seizure related death (probably drowning) within 1 month of starting PGB. Conclusion Pregabalin seems to be an effective and well-tolerated anti-epileptic drug when used as add-on treatment in patients with refractory partial epilepsy.

Seizure control and side-effect profile after switching adult epileptic patients from standard to extended-release divalproex sodium

Objectives To assess changes in seizure frequency, medication side-effects (especially tremor) and formulation preference after switching patients overnight from immediate-release to extended-release divalproex sodium. Methods Prospective evaluation of consecutive adult outpatients at an urban public hospital who were followed for 6 months after switching drug formulations. Seizure frequency was estimated from patient self-reports. Medication side-effects were monitored with a structured interview (tremor, fatigue, GI upset, hair loss), physician exam (nystagmus, tremor), a drawing test (tremor) and a specific 25-item questionnaire assessing the impact of tremor on activities of daily living. Results Forty-seven patients were included in the study but six patients were either lost to follow-up or had insufficient data. Seizure frequency and side-effect profile did not change significantly after switching drug formulations. However, patients had significant subjective improvement in their tremor with the extended-release formulation as assessed by the 25-item questionnaire ( p = 0.009 at 3 months and p = 0.04 at 6 months); other measures of tremor severity showed no change during the 6-month follow-up period. Most patients (71%) preferred the extended-release formulation. Conclusion Patients with epilepsy can be switched overnight from standard to extended-release divalproex sodium, without significant change in seizure frequency and drug side-effect profile. Most patients prefer the extended-release formulation, in part due to subjective decrease in tremor during daily activities.

Effects of SC58236, a selective COX-2 inhibitor, on epileptogenesis and spontaneous seizures in a rat model for temporal lobe epilepsy

Inflammation is an important biological process that is activated after status epilepticus and could be implicated in the development of epilepsy. Here we tested whether an anti-inflammatory treatment with a selective cox-2 inhibitor (SC58236) could prevent the development of epilepsy or modify seizure activity during the chronic epileptic phase. SC58236 was orally administered (10mg/kg) during the latent period for 7 days, starting 4h after electrically induced SE. Seizures were monitored using EEG/video monitoring until 35 days after SE. Cell death and inflammation were investigated using immunocytochemistry (NeuN and Ox-42). Sprouting was studied using Timm's staining after 1 week and after 4-5 months when rats were chronic epileptic. SC58236 was also administered during 5 days in chronic epileptic rats. Hippocampal EEG seizures were continuously monitored before, during and after treatment. SC58236 effectively reduced PGE(2) production but did not modify seizure development or the extent of cell death or microglia activation in the hippocampus. SC58236 treatment in chronic epileptic rats did not show any significant change in seizure duration or frequency of daily seizures. The fact that cox-2 inhibition, which effectively reduced prostaglandin levels, did not modify epileptogenesis or chronic seizure activity suggests that this type of treatment (starting after SE) will not provide an effective anti-epileptogenic or anti-epileptic therapy.

Seizure control in patients with epilepsy: the physician vs. medication factors.

BackgroundLittle is known about the relationship between types of healthcare providers and outcomes in patients with epilepsy. This study compares the relative effects of provider type (epileptologist vs. other neurologist) and pharmacologic treatment (newer vs. older antiepileptic drugs) on seizure control in patients with epilepsy.MethodsWe conducted a retrospective study of patients with medication-resistant epilepsy. Consecutive charts of 200 patients were abstracted using a standard case report form. For each patient, data included seizure frequency and medication use prior to, and while being treated by an epileptologist. Changes in seizure frequency were modeled using a generalized linear model.ResultsAfter transferring care from a general neurologist to specialized epilepsy center, patients experienced fewer seizures (p < 0.001) and were more frequently seizure-free (p < 0.001). The improved seizure control was not related to treatment with newer vs. older antiepileptic drugs (p = 0.305).ConclusionOur findings suggest an association between subspecialty epilepsy care and improved seizure control in patients with medication-resistant epilepsy. Further research should prospectively determine whether patients with medication-resistant epilepsy would benefit from being routinely referred to an epilepsy specialist.

Stress, anxiety, depression, and epilepsy: Investigating the relationship between psychological factors and seizures

The goal of the study described here was to examine the interrelationship between psychological factors (anxiety, stress, and depression) and seizures. In this longitudinal cohort study, data on anxiety, depression, perceived stress, and seizure recency (time since last seizure) and frequency were collected at two time points using standard validated questionnaire measures. Empirically based models with psychological factors explaining change in (1) seizure recency and (2) seizure frequency scores across time were specified. We then tested how these psychological factors acted together in predicting seizure recency and frequency. Our data were used to test whether these models were valid for the study population. Latent variable structural equation modeling was used for the analysis. Four hundred thirty-three of the 558 individuals who initially consented to participate provided two waves of data for this analysis. Stress (beta=0.25, P<0.01), anxiety (beta=0.30, P<0.01), and depression (beta=0.30, P<0.01) all predicted change in seizure recency. However, it was depression that mediated the relationship of both anxiety and stress with modeled change in seizure recency (beta=0.19, P<0.01) and seizure frequency (beta=0.30, P<0.01) over time. Depression mediates the relationship between stress and anxiety and change in seizure recency and seizure frequency. These findings highlight the importance of depression management in addition to seizure management in the assessment and treatment of epilepsy in an adult population.

Randomized Controlled Trial of Traditional Chinese Medicine (Acupuncture and Tuina) in Cerebral Palsy: Part 1—Any Increase in Seizure in Integrated Acupuncture and Rehabilitation Group Versus Rehabilitation Group?

The objective of this study was to observe for any change in baseline seizure frequency with acupuncture in children with cerebral palsy. A randomized controlled study was conducted: Group I consisted of integrated acupuncture, tuina, and rehabilitation (physiotherapy, occupational therapy, and hydrotherapy) for 12 weeks; and Group II consisted of rehabilitation (physiotherapy, occupational therapy, and hydrotherapy) for 12 weeks. After a washout period of 4 weeks, Group II then received acupuncture and tuina for 12 weeks. Each subject received 5 daily acupuncture sessions per week for 12 weeks (total = 60 sessions). All children were assessed for any change in seizure frequency during treatment. One hundred and sixteen (116) children were recruited and randomized into Group I (N = 58) and Group II (N = 58). Thirty-three (33) children withdrew (9 from Group I and 24 from Group II). Of the remaining 83 children, Group I consisted of 49 and Group II of 34 children. For baseline, 5 children (6%; 5/83) had seizures. During phase 1 (12 weeks) of integrative treatment and subsequent 4-week follow-up, 3 children in Group I had seizures. Among those 3 children with seizures, 1 child with prior history of recurrent febrile seizure had 3 more recurrent febrile seizures during acupuncture treatment and 2 children without any prior history of seizures had new-onset seizures (1 with 3 recurrent febrile seizures and 1 with afebrile seizure). For Group I, 2 children with epilepsy had no increase in seizure frequency during acupuncture treatment. For Group II during the phase 2 acupuncture period, none had increase in seizure frequency. In both groups, 4 of 5 children (80%; 2 in Group I and 2 in Group II) with seizures had no increase in seizure frequency during acupuncture treatment and follow-up. The risk of increasing seizure is not increased with acupuncture treatment for cerebral palsy.

Outcomes Remain Ambivalent for Deep Brain Stimulation and Epilepsy

Deep Brain Stimulation in Patients with Refractory Temporal Lobe Epilepsy. Boon P, Vonck K, De Herdt V, Van Dycke A, Goethals M, Goossens L, Van Zandijcke M, De Smedt T, Dewaele I, Achten R, Wadman W, Dewaele F, Caemaert J, Van Roost D. Epilepsia 2007;48(8):1551–1560. PURPOSE: This pilot study prospectively evaluated the efficacy of long-term deep brain stimulation (DBS) in medial temporal lobe (MTL) structures in patients with MTL epilepsy. METHODS: Twelve consecutive patients with refractory MTL epilepsy were included in this study. The protocol included invasive video-EEG monitoring for ictal-onset localization and evaluation for subsequent stimulation of the ictal-onset zone. Side effects and changes in seizure frequency were carefully monitored. RESULTS: Ten of 12 patients underwent long-term MTL DBS. Two of 12 patients underwent selective amygdalohippocampectomy. After mean follow-up of 31 months (range, 12–52 months), one of 10 stimulated patients are seizure-free (&gt;1 year), one of 10 patients had a &gt;90% reduction in seizure frequency; five of 10 patients had a seizure-frequency reduction of ≥50%; two of 10 patients had a seizure-frequency reduction of 30–49%; and one of 10 patients was a nonresponder. None of the patients reported side effects. In one patient, MRI showed asymptomatic intracranial hemorrhages along the trajectory of the DBS electrodes. None of the patients showed changes in clinical neurological testing. Patients who underwent selective amygdalohippocampectomy are seizure-free (&gt;1 year), AEDs are unchanged, and no side effects have occurred. CONCLUSIONS: This open pilot study demonstrates the potential efficacy of long-term DBS in MTL structures that should now be further confirmed by multicenter randomized controlled trials.

Ambiguous results of an attempt to withdraw barbiturates in epilepsy patients with intellectual disability

Phenobarbital and primidone frequently have adverse effects on mental functions. Therefore, an attempt was made to taper barbiturates in 85 patients out of a resident population with epilepsy and intellectual disability who were selected according to clinical criteria. The objectives were to reduce the use of barbiturates, to improve the patients’ cognitive and psychological state, and to reduce polypharmacy while avoiding seizure exacerbation. Four months after complete withdrawal changes in seizure frequency were assessed as well as changes in cognitive abilities, psychological state and behaviour (using the clinical global impression scale). In 13 patients the tapering failed due to complications (seizure increase in 11 patients). In 72 patients the barbiturate was completely withdrawn (mean duration of tapering: 393 days). Cognitive improvement was achieved in 17 patients (23.6%), 5 patients (6.9%) deteriorated. Seizure frequency remained unchanged in 33 patients (45.8%), in another 15 patients (20.8%) the seizure frequency decreased. Reduction in polypharmacy was obtained in 61 patients (84.7%). In an overall judgement (clinical global impression scale) of cognitive abilities AND seizure control, 25 patients (34.7%) were improved. 31 patients (43.1%) remained unchanged while 12 patients deteriorated (4 patients: impossible to judge). For statistical analysis three outcome groups were defined: the improved group ( N = 25), the unchanged group ( N = 31), and the deteriorated/failed group ( N = 25) consisting of the 12 deteriorated patients plus the 13 patients in whom tapering failed. Stepwise logistic regression revealed a history of an attempt to withdraw phenobarbital/primidone ( p = 0.017; OR 3.8), age ( p = 0.012) and seizure frequency (marginally significant: p = 0.097) as outcome predictors. Older age was associated with better outcome. A high seizure frequency before tapering was related to good outcome, while seizure freedom and a history of failed withdrawal were associated with deterioration/failure. Outcome did not depend on duration of barbiturate therapy, dosage or serum concentration, co-medication, reduction rate, degree of intellectual disability, or epilepsy syndrome. In summary, the number of barbiturate medications has been considerably reduced, but the principal aim of the project, to relieve patients from assumed barbiturate side effects, has been achieved only in one out of four patients.

Epilepsy in older women

Women suffering from epilepsy require special attention throughout their life. In this review, management of epilepsy during the periods of perimenopause, menopause and late maturity is discussed. The effect of epilepsy on age at menopause, changes in seizure frequency during perimenopause and menopause, and the risks of hormone replacement therapy are also presented. Altered antiepileptic drug pharmacokinetics with increasing age and the management of this vulnerable population is also discussed.

Hormone replacement therapy: Will it affect seizure control and AED levels?

Interest in the years of reproductive changes for women with epilepsy (WWE), specifically perimenopause, menopause and postmenopause has been emerging in the epilepsy community. This article discusses evidence for changes in seizure frequency during perimenopause and postmenopause. Further, a catamenial epilepsy pattern during the reproductive years may be a hallmark for the observed seizure frequency change during these years; that is, an increase at perimenopause but a decrease at menopause. This finding implies that a subset of WWE are particularly susceptible to endogenous reproductive hormonal changes. An adverse effect on seizure frequency with the use of hormone replacement therapy (HRT) during postmenopause for WWE was reported in questionnaires, and was later borne out in a clinical trial. The laboratory counterpart of this human trial, HRT in ovariectomized rodent seizure models, shows that estrogen and progesterone are neuroprotective and do not uniformly increase seizure frequency. Possible reasons for the discrepancy between "the lab and the clinic" are presented. Strategies for managing HRT in symptomatic postmenopausal WWE using estrogenic and progestogenic compounds that may be less likely to promote seizures are discussed.

Therapeutic Effects of Vagus Nerve Stimulation in Intractable Childhood Epilepsy: Experience for 12 Months after VNS Implantation

Vagus nerve stimulation (VNS) is presently considered an effective mode of treatment in intractable epilepsy. Its efficacy in children, however, has not been as well studied. This study was performed to evaluate the efficacy of the procedure in the pediatric age group. 6 patients who received VNS implantation in Chonnam National University Hospital from July 2006 to February 2008 have been evaluated about the efficacy of seizure control and the presence of side effects after VNS implantation for more than a year at least. Mean age of the patients at the time of VNS implantation were 10 years 3 months. Mean duration of follow-up was 14 months. Six patients included three cases with Lennox-Gastaut syndromes, one generalized tonic seizure, one generalized tonic clonic seizure, and one complex partial seizure. Three patients showed more than 50% reduction in seizure frequency compared with baseline at 3 months after the implantation. Among them, one showed complete seizure ablation, another showed no change in seizure frequency and the other showed increased frequency of seizure at 9 months after the implantation. The other three patients showed no change in seizure frequency. One of them, however, showed reduction of seizure intensity. Cough (2 cases), hoarseness (2), and wobbling voice (1) developed after VNS implantation. Most of these adverse effects disappeared without any treatment. In this study, one patient showed complete seizure ablation, but VNS was insignificant in five patients. Long-term follow up and adjustment of parameters such as output current, duty cycle are in need.

Melatonin treatment in individuals with intellectual disability and chronic insomnia: a randomized placebo‐controlled study

While several small-number or open-label studies suggest that melatonin improves sleep in individuals with intellectual disabilities (ID) with chronic sleep disturbance, a larger randomized control trial is necessary to validate these promising results. The effectiveness of melatonin for the treatment of chronic sleep disturbance was assessed in a randomized double-blind placebo-controlled trial with 51 individuals with ID. All of these individuals presented with chronic ideopatic sleep disturbance for more than 1 year. The study consisted of a 1-week baseline, followed by 4 weeks of treatment. Parents or other caregivers recorded lights off time, sleep onset time, night waking, wake up time and epileptic seizures. Endogenous melatonin cycle was measured in saliva before and after treatment. Compared with placebo, melatonin significantly advanced mean sleep onset time by 34 min, decreased mean sleep latency by 29 min, increased mean total sleep time by 48 min, reduced the mean number of times the person awoke during the night by 0.4, decreased the mean duration of these night waking periods by 17 min and advanced endogenous melatonin onset at night by an average of 2.01 h. Lights off time, sleep offset time and the number of nights per week with night waking did not change. Only few minor or temporary adverse reactions and no changes in seizure frequency were reported. Melatonin treatment improves some aspects of chronic sleep disturbance in individuals with ID.